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EFFECT OF FLUOXETINE ON MAXIMAL ELECTROSHOCK SEIZURES IN MICE: ACUTE VS CHRONIC ADMINISTRATION
Pharmacological Research, Vol. 39, No. 6, 1999 Article No. phrs.1999.0466, available online at http:rrwww.idealibrary.com on
EFFECT OF FLUOXETINE ON MAXIMAL ELECTROSHOCK SEIZURES IN MICE: ACUTE VS CHRONIC ADMINISTRATION S.S. RAJU a,U , A.R. NOORa , S. GURTHU a , C.R. GIRIYAPPANAVARa , S.B. ACHARYAa , H.C. LOW b and S.H. QUAH b a
Department of Pharmacology, School of Medical Sciences, Uni¨ ersiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia and bSchool of Mathematical Sciences, Uni¨ ersiti Sains Malaysia, Penang, Malaysia Accepted 18 January 1999
There are no definite reports regarding the effects of chronic fluoxetine on animal models of epilepsy. Since chronically administered fluoxetine, in comparison to acutely administered fluoxetine has different effects on CNS, the present study was undertaken to investigate the effect of acute and chronic fluoxetine pretreatment, on a median anticonvulsant dose ŽED50 . of phenytoin in male ICR albino mice. Additionally, the effects of fluoxetine pretreatment on median convulsive current ŽCC 50 . in the presence and absence of phenytoin were investigated and results were compared. The maximal electroshock seizure ŽMES. test was used to estimate the ED50 of phenytoin. The electroshock threshold test was used to estimate CC 50 . ED50 and CC 50 values were calculated by probit analysis. The effects of the chronic and acute fluoxetine groups on the ED50 of phenytoin were significantly different Ž P- 0.05., and on CC 50 this difference was not statistically significant. Chronic fluoxetine insignificantly increased the ED50 of phenytoin and decreased the CC 50 while acute fluoxetine decreased the ED50 of phenytoin and increased the CC 50 . Our results indicate that chronic fluoxetine does not have an antiepileptic property and it may have dubious proconvulsant properties, contrary to acute fluoxetine. Q 1999 Academic Press
KEY
WORDS:
fluoxetine, maximal electroshock seizures, ED50 of phenytoin, CC 50 , chronic administration.
INTRODUCTION
The use of antidepressant drugs in epileptic patients has been a concern for clinicians because of reports that these drugs have proconvulsant or frank convulsant effects w1x. Fluoxetine, a selective serotonin reuptake inhibitor ŽSRI., has been reported to be epileptogenic w1]4x. Experimental studies however, showed that fluoxetine has an anticonvulsant effect w5, 6x, and that the anticonvulsant effects of some
U
Corresponding author.
1043]6618r99r060451]04r$30.00r0
antiepileptic drugs are enhanced by addition of fluoxetine w7x. In all experimental studies single dose fluoxetine was administered 30]60 min before the test was performed. It appears that no study has been conducted to determine the effect of chronically administered fluoxetine on epileptic seizures and its interaction with antiepileptics. Chronically administered fluoxetine has different effects, compared to acutely administered fluoxetine on CNS w8x. From a therapeutic point of view, the effect of chronic administration is more appropriate. The objectives of the present study include: Ž1. to determine whether fluoxetine is a proconvulsant or anticonvulsant after acute and chronic administraQ 1999 Academic Press
Pharmacological Research, Vol. 39, No. 6, 1999
452
tion and, Ž2. to determine the effects of acute and chronic administration of fluoxetine on the antiepileptic effect of phenytoin.
MATERIALS AND METHODS
Animals and experimentation Male ICR mice weighing 20]26 g were used in this study after at least 1 week of acclimatization. The animals were housed in groups of ten in cages under standard laboratory conditions and maintained on a natural light]dark cycle. All experiments were performed at the same time of the day to minimise circadian influences. Control and drug experiments were done on the same day to avoid day-to-day variations in convulsive susceptibility. Each mouse was used only once.
Drugs The following drugs were used: fluoxetine ŽEli Lilly, Basingstoke, England. and phenytoin sodium ŽParke Davis, Caringbah, N.S.W., Australia.. In acute fluoxetine studies, fluoxetine was dissolved in sterile saline and administered intraperitonially Ži.p.. 60 min before the tests; and in chronic fluoxetine studies, it was dissolved in water Žfinal concentration of 50 m g mly1 . and administered in the form of drinking water Žon average each mouse consumes 4]8 ml of water per day.. Phenytoin sodium was dissolved in water and administered intraperitonially Ži.p.., 30 min before the tests. The volume of all injected solutions was 0.01 ml gy1 .
Maximal electroshock seizure (MES ) test One hundred mice were divided into ten groups, with ten in each group. Five groups received fluoxetine 10 mg kgy1 dayy1 orally for 21 days and the other 5 groups Žcontrol. received nothing. Control and fluoxetine groups received phenytoin in incremental doses of 2, 4, 8, 12, 16 mg kgy1 i.p., 30 min before testing. Seizures were induced by delivery of a 50-mA intensity current for 0.2 s through ear-clip electrodes. Mice which did not exhibit hind limb tonic extensor response were considered protected. The ED50 Žmedian effective dose. of phenytoin and 95% confidence intervals were calculated by probit analysis using the statistical package SPSS for Windows, Version 6, from the dose]effect data.
Electroshock threshold test Two hundred mice were divided into 20 groups, ten in each group and drugs were administered as follows: Groups 1]5 Žfluoxetine., Groups 6]10 Žcontrol., Groups 11]15 Žfluoxetine q phenytoin. and Groups 16]20 Žphenytoin.. Fluoxetine 10 mg kgy1 , was given as a daily oral dose Žfirst day dose i.p.. for 21 days before the test. Phenytoin 5 mg kgy1 was given i.p., 30 min before testing. The amperage
necessary to cause the hind limb tonic extensor component of seizures in 50% of animals ŽCC 50 s convulsive current 50. was determined. To determine CC 50 , current strengths varying from 10 to 100 mA were used. The CC 50 and 95% confidence intervals were calculated by probit analysis using SPSS from the dose]effect data. Both the tests were carried out on day 1 Žafter a single dose of fluoxetine. and day 22 Žafter 21 days fluoxetine administration..
RESULTS
Effect of fluoxetine on ED50 of phenytoin The difference between chronic and acute groups of fluoxetine on ED50 of phenytoin was significant Ž P- 0.05.. When fluoxetine treated animals were compared with the control animals, chronic fluoxetine insignificantly increased ED50 of phenytoin from 7.1 Ž5.6]8.6. mg kgy1 to 9.4 Ž7.6]11.4. mg kgy1 , while acute fluoxetine decreased the ED50 from 7.0 Ž5.5]8.7. mg kgy1 to 5.2 Ž4.0]6.6. mg kgy1 Žsee Table I and Fig. 1..
Effect of fluoxetine on seizure threshold (CC50 ) The difference between chronic and acute groups of fluoxetine on CC 50 was not statistically significant. When fluoxetine treated animals were compared with control animals, chronic fluoxetine insignificantly decreased the CC 50 from 26.2 Ž20.8]32.9. mA to 23.1 Ž18.4]29.1. mA, while acute fluoxetine increased the CC 50 from 26.1 Ž20.5]33.1. mA to 32.9 Ž26.3]40.7. mA Žsee Table II and Fig. 2.. When the fluoxetine q phenytoin group was compared with the phenytoin group, chronic fluoxetine insignificantly decreased the CC 50 from 48.7 Ž40.0]58.1. mA to 41.3 Ž33.3]50.3. mA, while acute fluoxetine increased the CC 50 from 48.2 Ž39.3]58.1. mA to 56.0 Ž46.1]67.2. mA Žsee Table II and Fig. 2..
DISCUSSION The results of the present study show that prolonged Ž chronic . fluoxetine administration has no
Table I Effect of acute and chronic fluoxetine on the median effective dose (ED50 ) of phenytoin and 95% confidential intervals. Groups
Acute Žday 1. mg kgy1
Chronic Žday 22. mg kgy1
Control Fluoxetine
7.0 Ž5.5]8.7. 5.2 Ž4.0]6.6.
7.1 Ž5.6]8.6. 9.4 Ž7.6]11.4.U
U
The difference between acute and chronic groups is statistically significant Ž P- 0.05..
Pharmacological Research, Vol. 39, No. 6, 1999
453
Fig. 2. Effect of acute and chronic fluoxetine on convulsive current in 50% ŽCC 50 ..
Fig. 1. Effect of acute and chronic fluoxetine on median anticonvulsive dose ŽED50 . of phenytoin.
antiepileptic activity; or it may have dubious proconvulsant activity. This finding differs from the reports which indicated anticonvulsant activity for single dose Žacute. fluoxetine w5]7x and upholds the report of Statnic et al. w9x. The study also shows dubious anticonvulsant activity after single dose Žacute. fluoxetine administration. Fluoxetine, a serotonin reuptake inhibitor is a commonly used antidepressant drug. Repeated treatment with serotonin reuptake inhibitors produce complex changes in serotonin receptors, including inconsistent loss of forebrain 5-HT1 or 5-HT2 receptors, with unclear consequences w1x. Presynaptic 5-HT autoreceptors Žtypes 1A or 1D. become desensitised after repeated exposure to serotonin re-uptake inhibitors w1x. Fluoxetine appears to decrease the turnover of serotonin in the CNS, probably as a result of a decrease in the rate of serotonin synthesis w10x. Depletion of brain serotonin exacerbates audiogenic seizures in genetically epilepsy-prone rats ŽGEPRs., while elevations in brain 5-HT attenuate these seizures w11x. Fluoxetine also inhibits spontaneous firing of the serotinergic
Table II Effect of acute and chronic fluoxetine on convulsive current in 50% (CC 50 ) and 95% confidence intervals Groups Control Fluoxetine Phenytoin Phenytoin q fluoxetine
Acute Žday 1. ŽmA.
Chronic Žday 22. ŽmA.
26.1 Ž20.5]33.1. 32.9 Ž26.3]40.7. 48.2 Ž39.3]58.1.
26.2 Ž20.8]32.9. 23.1 Ž18.4]29.1. 48.7 Ž40.0]58.1.
56.0 Ž46.1]67.2.
41.3 Ž33.3]50.3.
neurons in the dorsal raphe nucleus w10x. Multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation w12x. Depletion of serotonin did not diminish the anticonvulsant effect of phenytoin in GEPRs w11x. After considering the reports mentioned above, the following possible explanation for our findings was postulated. The dubious anti-convulsant effect of acute fluoxetine could be related to either decreased firing rates of serotinergic neurons due to stimulation of presynaptic 5-HT1A receptors, which are predominantly inhibitory in nature, or due to post-synaptic 5-HT2 receptor stimulation. Ineffectiveness or dubious proconvulsant activity for chronic fluoxetine could be related to either increased firing of serotinergic neurons due to down regulation of presynaptic 5-HT1A receptors, or due to down regulation of post-synaptic 5-HT2 receptors. Our conclusions are; Ž1. acute and chronic fluoxetine administration have different Žopposite. effects on epileptic seizures; and Ž2. long-term fluoxetine administration does not have an anticonvulsant property similar to that of acute fluoxetine reported earlier by some researchers.
ACKNOWLEDGEMENTS This study was supported by IRPA short-term grants ŽGrant no. 391r961r1017. from the Ministry of Science, Technology and the Environment through The School of Medical Sciences, Universiti Sains Malaysia.
REFERENCES 1. Baldessarini RJ. Drugs and treatment of psychiatric disorders. In: Goodman and Gilman’s the Pharmacological Basis of Therapeutics. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. McGraw-Hill 1996: 431]59. 2. Curran S. Effect of paroxetine on seizure length during electroconvulsive therapy. Acta Psychiatr Scand 1995; 92: 239]40.
454
3. Weber JJ. Seizure activity associated with fluoxetine therapy. Clin Pharm 1989; 8: 296]8. 4. Ware MR, Stewart RB. Seizures associated with fluoxetine therapy. Ann Pharmacother 1989; 23: 428. 5. Pasini A, Tortorella A, Gale K. Anticonvulsant effect of intranigral fluoxetine. Brain Res 1992; 593: 287]90. 6. Prendeville S, Gale K. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures. Epilepsia 1993; 34: 381]4. 7. Leander JD. Fluoxetine, a selective serotonin uptake inhibitor, enhances the anticonvulsive effects of phenytoin, carbamazepine and ameltolide. Epilepsia 1992; 33: 573]6. 8. Borsini F. Balance between cortical 5HTIA and 5HT2 receptor function: Hypothesis for a faster antidepressant action. Pharmacol Res 1994; 30: 1]11.
Pharmacological Research, Vol. 39, No. 6, 1999
9. Statnic M, Daily J, Jobe P, Browning R. Neither intranigral fluoxetine nor 5,7-dihydroxytryptamine alter audiogenic seizures in genetically epilepsy-prone rats. Eur J Pharmacol 1996; 299: 93]102. 10. Antidepressants: fluoxetine. In: AHFS Drug Information. McEvoy GK, Litvak K, Welsh Jr OH, eds. American Society of Health-system Pharmacists Inc. 1996: 1594. 11. Daily JW, Yan QS, Adams-Curtis LE, Ryu JR, Ko KH, Misra PK, Jobe PC. Neurochemical correlates of antiepileptic drugs in genetically epilepsy-prone rat ŽGEPR.. Life Sci 1995; 58: 259]66. 12. Pasini A, Tortorella A, Gale K. Anticonvulsant effect of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res 1996; 724: 84]8.
EFFECT OF FLUOXETINE ON MAXIMAL ELECTROSHOCK SEIZURES IN MICE: ACUTE VS CHRONIC ADMINISTRATION S.S. RAJU a,U , A.R. NOORa , S. GURTHU a , C.R. GIRIYAPPANAVARa , S.B. ACHARYAa , H.C. LOW b and S.H. QUAH b a
Department of Pharmacology, School of Medical Sciences, Uni¨ ersiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia and bSchool of Mathematical Sciences, Uni¨ ersiti Sains Malaysia, Penang, Malaysia Accepted 18 January 1999
There are no definite reports regarding the effects of chronic fluoxetine on animal models of epilepsy. Since chronically administered fluoxetine, in comparison to acutely administered fluoxetine has different effects on CNS, the present study was undertaken to investigate the effect of acute and chronic fluoxetine pretreatment, on a median anticonvulsant dose ŽED50 . of phenytoin in male ICR albino mice. Additionally, the effects of fluoxetine pretreatment on median convulsive current ŽCC 50 . in the presence and absence of phenytoin were investigated and results were compared. The maximal electroshock seizure ŽMES. test was used to estimate the ED50 of phenytoin. The electroshock threshold test was used to estimate CC 50 . ED50 and CC 50 values were calculated by probit analysis. The effects of the chronic and acute fluoxetine groups on the ED50 of phenytoin were significantly different Ž P- 0.05., and on CC 50 this difference was not statistically significant. Chronic fluoxetine insignificantly increased the ED50 of phenytoin and decreased the CC 50 while acute fluoxetine decreased the ED50 of phenytoin and increased the CC 50 . Our results indicate that chronic fluoxetine does not have an antiepileptic property and it may have dubious proconvulsant properties, contrary to acute fluoxetine. Q 1999 Academic Press
KEY
WORDS:
fluoxetine, maximal electroshock seizures, ED50 of phenytoin, CC 50 , chronic administration.
INTRODUCTION
The use of antidepressant drugs in epileptic patients has been a concern for clinicians because of reports that these drugs have proconvulsant or frank convulsant effects w1x. Fluoxetine, a selective serotonin reuptake inhibitor ŽSRI., has been reported to be epileptogenic w1]4x. Experimental studies however, showed that fluoxetine has an anticonvulsant effect w5, 6x, and that the anticonvulsant effects of some
U
Corresponding author.
1043]6618r99r060451]04r$30.00r0
antiepileptic drugs are enhanced by addition of fluoxetine w7x. In all experimental studies single dose fluoxetine was administered 30]60 min before the test was performed. It appears that no study has been conducted to determine the effect of chronically administered fluoxetine on epileptic seizures and its interaction with antiepileptics. Chronically administered fluoxetine has different effects, compared to acutely administered fluoxetine on CNS w8x. From a therapeutic point of view, the effect of chronic administration is more appropriate. The objectives of the present study include: Ž1. to determine whether fluoxetine is a proconvulsant or anticonvulsant after acute and chronic administraQ 1999 Academic Press
Pharmacological Research, Vol. 39, No. 6, 1999
452
tion and, Ž2. to determine the effects of acute and chronic administration of fluoxetine on the antiepileptic effect of phenytoin.
MATERIALS AND METHODS
Animals and experimentation Male ICR mice weighing 20]26 g were used in this study after at least 1 week of acclimatization. The animals were housed in groups of ten in cages under standard laboratory conditions and maintained on a natural light]dark cycle. All experiments were performed at the same time of the day to minimise circadian influences. Control and drug experiments were done on the same day to avoid day-to-day variations in convulsive susceptibility. Each mouse was used only once.
Drugs The following drugs were used: fluoxetine ŽEli Lilly, Basingstoke, England. and phenytoin sodium ŽParke Davis, Caringbah, N.S.W., Australia.. In acute fluoxetine studies, fluoxetine was dissolved in sterile saline and administered intraperitonially Ži.p.. 60 min before the tests; and in chronic fluoxetine studies, it was dissolved in water Žfinal concentration of 50 m g mly1 . and administered in the form of drinking water Žon average each mouse consumes 4]8 ml of water per day.. Phenytoin sodium was dissolved in water and administered intraperitonially Ži.p.., 30 min before the tests. The volume of all injected solutions was 0.01 ml gy1 .
Maximal electroshock seizure (MES ) test One hundred mice were divided into ten groups, with ten in each group. Five groups received fluoxetine 10 mg kgy1 dayy1 orally for 21 days and the other 5 groups Žcontrol. received nothing. Control and fluoxetine groups received phenytoin in incremental doses of 2, 4, 8, 12, 16 mg kgy1 i.p., 30 min before testing. Seizures were induced by delivery of a 50-mA intensity current for 0.2 s through ear-clip electrodes. Mice which did not exhibit hind limb tonic extensor response were considered protected. The ED50 Žmedian effective dose. of phenytoin and 95% confidence intervals were calculated by probit analysis using the statistical package SPSS for Windows, Version 6, from the dose]effect data.
Electroshock threshold test Two hundred mice were divided into 20 groups, ten in each group and drugs were administered as follows: Groups 1]5 Žfluoxetine., Groups 6]10 Žcontrol., Groups 11]15 Žfluoxetine q phenytoin. and Groups 16]20 Žphenytoin.. Fluoxetine 10 mg kgy1 , was given as a daily oral dose Žfirst day dose i.p.. for 21 days before the test. Phenytoin 5 mg kgy1 was given i.p., 30 min before testing. The amperage
necessary to cause the hind limb tonic extensor component of seizures in 50% of animals ŽCC 50 s convulsive current 50. was determined. To determine CC 50 , current strengths varying from 10 to 100 mA were used. The CC 50 and 95% confidence intervals were calculated by probit analysis using SPSS from the dose]effect data. Both the tests were carried out on day 1 Žafter a single dose of fluoxetine. and day 22 Žafter 21 days fluoxetine administration..
RESULTS
Effect of fluoxetine on ED50 of phenytoin The difference between chronic and acute groups of fluoxetine on ED50 of phenytoin was significant Ž P- 0.05.. When fluoxetine treated animals were compared with the control animals, chronic fluoxetine insignificantly increased ED50 of phenytoin from 7.1 Ž5.6]8.6. mg kgy1 to 9.4 Ž7.6]11.4. mg kgy1 , while acute fluoxetine decreased the ED50 from 7.0 Ž5.5]8.7. mg kgy1 to 5.2 Ž4.0]6.6. mg kgy1 Žsee Table I and Fig. 1..
Effect of fluoxetine on seizure threshold (CC50 ) The difference between chronic and acute groups of fluoxetine on CC 50 was not statistically significant. When fluoxetine treated animals were compared with control animals, chronic fluoxetine insignificantly decreased the CC 50 from 26.2 Ž20.8]32.9. mA to 23.1 Ž18.4]29.1. mA, while acute fluoxetine increased the CC 50 from 26.1 Ž20.5]33.1. mA to 32.9 Ž26.3]40.7. mA Žsee Table II and Fig. 2.. When the fluoxetine q phenytoin group was compared with the phenytoin group, chronic fluoxetine insignificantly decreased the CC 50 from 48.7 Ž40.0]58.1. mA to 41.3 Ž33.3]50.3. mA, while acute fluoxetine increased the CC 50 from 48.2 Ž39.3]58.1. mA to 56.0 Ž46.1]67.2. mA Žsee Table II and Fig. 2..
DISCUSSION The results of the present study show that prolonged Ž chronic . fluoxetine administration has no
Table I Effect of acute and chronic fluoxetine on the median effective dose (ED50 ) of phenytoin and 95% confidential intervals. Groups
Acute Žday 1. mg kgy1
Chronic Žday 22. mg kgy1
Control Fluoxetine
7.0 Ž5.5]8.7. 5.2 Ž4.0]6.6.
7.1 Ž5.6]8.6. 9.4 Ž7.6]11.4.U
U
The difference between acute and chronic groups is statistically significant Ž P- 0.05..
Pharmacological Research, Vol. 39, No. 6, 1999
453
Fig. 2. Effect of acute and chronic fluoxetine on convulsive current in 50% ŽCC 50 ..
Fig. 1. Effect of acute and chronic fluoxetine on median anticonvulsive dose ŽED50 . of phenytoin.
antiepileptic activity; or it may have dubious proconvulsant activity. This finding differs from the reports which indicated anticonvulsant activity for single dose Žacute. fluoxetine w5]7x and upholds the report of Statnic et al. w9x. The study also shows dubious anticonvulsant activity after single dose Žacute. fluoxetine administration. Fluoxetine, a serotonin reuptake inhibitor is a commonly used antidepressant drug. Repeated treatment with serotonin reuptake inhibitors produce complex changes in serotonin receptors, including inconsistent loss of forebrain 5-HT1 or 5-HT2 receptors, with unclear consequences w1x. Presynaptic 5-HT autoreceptors Žtypes 1A or 1D. become desensitised after repeated exposure to serotonin re-uptake inhibitors w1x. Fluoxetine appears to decrease the turnover of serotonin in the CNS, probably as a result of a decrease in the rate of serotonin synthesis w10x. Depletion of brain serotonin exacerbates audiogenic seizures in genetically epilepsy-prone rats ŽGEPRs., while elevations in brain 5-HT attenuate these seizures w11x. Fluoxetine also inhibits spontaneous firing of the serotinergic
Table II Effect of acute and chronic fluoxetine on convulsive current in 50% (CC 50 ) and 95% confidence intervals Groups Control Fluoxetine Phenytoin Phenytoin q fluoxetine
Acute Žday 1. ŽmA.
Chronic Žday 22. ŽmA.
26.1 Ž20.5]33.1. 32.9 Ž26.3]40.7. 48.2 Ž39.3]58.1.
26.2 Ž20.8]32.9. 23.1 Ž18.4]29.1. 48.7 Ž40.0]58.1.
56.0 Ž46.1]67.2.
41.3 Ž33.3]50.3.
neurons in the dorsal raphe nucleus w10x. Multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation w12x. Depletion of serotonin did not diminish the anticonvulsant effect of phenytoin in GEPRs w11x. After considering the reports mentioned above, the following possible explanation for our findings was postulated. The dubious anti-convulsant effect of acute fluoxetine could be related to either decreased firing rates of serotinergic neurons due to stimulation of presynaptic 5-HT1A receptors, which are predominantly inhibitory in nature, or due to post-synaptic 5-HT2 receptor stimulation. Ineffectiveness or dubious proconvulsant activity for chronic fluoxetine could be related to either increased firing of serotinergic neurons due to down regulation of presynaptic 5-HT1A receptors, or due to down regulation of post-synaptic 5-HT2 receptors. Our conclusions are; Ž1. acute and chronic fluoxetine administration have different Žopposite. effects on epileptic seizures; and Ž2. long-term fluoxetine administration does not have an anticonvulsant property similar to that of acute fluoxetine reported earlier by some researchers.
ACKNOWLEDGEMENTS This study was supported by IRPA short-term grants ŽGrant no. 391r961r1017. from the Ministry of Science, Technology and the Environment through The School of Medical Sciences, Universiti Sains Malaysia.
REFERENCES 1. Baldessarini RJ. Drugs and treatment of psychiatric disorders. In: Goodman and Gilman’s the Pharmacological Basis of Therapeutics. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. McGraw-Hill 1996: 431]59. 2. Curran S. Effect of paroxetine on seizure length during electroconvulsive therapy. Acta Psychiatr Scand 1995; 92: 239]40.
454
3. Weber JJ. Seizure activity associated with fluoxetine therapy. Clin Pharm 1989; 8: 296]8. 4. Ware MR, Stewart RB. Seizures associated with fluoxetine therapy. Ann Pharmacother 1989; 23: 428. 5. Pasini A, Tortorella A, Gale K. Anticonvulsant effect of intranigral fluoxetine. Brain Res 1992; 593: 287]90. 6. Prendeville S, Gale K. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures. Epilepsia 1993; 34: 381]4. 7. Leander JD. Fluoxetine, a selective serotonin uptake inhibitor, enhances the anticonvulsive effects of phenytoin, carbamazepine and ameltolide. Epilepsia 1992; 33: 573]6. 8. Borsini F. Balance between cortical 5HTIA and 5HT2 receptor function: Hypothesis for a faster antidepressant action. Pharmacol Res 1994; 30: 1]11.
Pharmacological Research, Vol. 39, No. 6, 1999
9. Statnic M, Daily J, Jobe P, Browning R. Neither intranigral fluoxetine nor 5,7-dihydroxytryptamine alter audiogenic seizures in genetically epilepsy-prone rats. Eur J Pharmacol 1996; 299: 93]102. 10. Antidepressants: fluoxetine. In: AHFS Drug Information. McEvoy GK, Litvak K, Welsh Jr OH, eds. American Society of Health-system Pharmacists Inc. 1996: 1594. 11. Daily JW, Yan QS, Adams-Curtis LE, Ryu JR, Ko KH, Misra PK, Jobe PC. Neurochemical correlates of antiepileptic drugs in genetically epilepsy-prone rat ŽGEPR.. Life Sci 1995; 58: 259]66. 12. Pasini A, Tortorella A, Gale K. Anticonvulsant effect of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res 1996; 724: 84]8.